Mechanisms of Regulated Cell Death: Current Perspectives.

Balancing cell survival and cell death is fundamental to development and homeostasis. Cell death is regulated by multiple interconnected signaling pathways and molecular mechanisms. Regulated cell death (RCD) is implicated in fundamental processes such as organogenesis and tissue remodeling, removal of unnecessary structures or cells, and regulation of cell numbers. RCD can also be triggered by exogenous perturbations of the intracellular or extracellular microenvironment when the adaptive processes that respond to stress fail. During the past few years, many novel forms of non-apoptotic RCD have been identified, and the characterization of RCD mechanisms at a molecular level has deepened our understanding of diseases encountered in human and veterinary medicine. Given the complexity of these processes, it has become clear that the identification of RCD cannot be based simply on morphologic characteristics and that descriptive and diagnostic terms presently used by pathologists-such as individual cell apoptosis or necrosis-appear inadequate and possibly misleading. In this review, the current understanding of the molecular machinery of each type of non-apoptotic RCD mechanisms is outlined. Due to the continuous discovery of new mechanisms or nuances of previously described processes, the limitations of the terms apoptosis and necrosis to indicate microscopic findings are also reported. In addition, the need for a standard panel of biomarkers and functional tests to adequately characterize the underlying RCD and its role as a mechanism of disease is considered.

Restricted Sensitivity of FJ-C Staining to Assess Neuronal Degeneration and Death in Preclinical Mouse Studies.

Fluorescein-derived fluorochromes and anionic dyes such as Fluoro-Jade (FJ) stains have been introduced to facilitate recognition of dying neurons in tissue sections. However, the definition of what is really detected by FJ-based stains and its sensitivity in the detection of neuronal cell death is unclear. In our work, we evaluated the outcome of FJ-C staining in mouse brains from 4 different well-characterized models of neurodegeneration. Neuronal degeneration and loss were highlighted with high sensitivity by FJ-C stain in mice with dysfunctional γ-secretase in the glutamatergic neurons and in mice affected by acute cerebral ischemia. Histopathologically, acute eosinophilic necrosis or "red dead" neurons were associated with FJ-C staining in both settings. Conversely, in mice affected by chronic cerebral microinfarcts due to tumor lysis syndrome as well as in a model of mitochondrial encephalopathy, FJ-C staining failed to detect neuronal death. Histopathologically, these models were characterized by extensive neuronal vacuolation associated with fading neurons ("ghost cells"). Therefore, contrary to the widespread belief that FJ-C stain has high affinity for all degenerating neurons regardless of the underlying cell death mechanism, we observed restricted sensitivity of the technique to specific conditions of neuronal cell death. As such, complementary techniques are essential to evaluate the presence of neurodegeneration in the absence of a positive FJ-C signal.

TET2-Dependent Hydroxymethylome Plasticity Reduces Melanoma Initiation and Progression.

Although numerous epigenetic aberrancies accumulate in melanoma, their contribution to initiation and progression remain unclear. The epigenetic mark 5-hydroxymethylcytosine (5hmC), generated through TET-mediated DNA modification, is now referred to as the sixth base of DNA and has recently been reported as a potential biomarker for multiple types of cancer. Loss of 5hmC is an epigenetic hallmark of melanoma, but whether a decrease in 5hmc levels contributes directly to pathogenesis or whether it merely results from disease progression-associated epigenetic remodeling remains to be established. Here, we show that NRAS-driven melanomagenesis in mice is accompanied by an overall decrease in 5hmC and specific 5hmC gains in selected gene bodies. Strikingly, genetic ablation of Tet2 in mice cooperated with oncogenic NRASQ61K to promote melanoma initiation while suppressing specific gains in 5hmC. We conclude that TET2 acts as a barrier to melanoma initiation and progression, partly by promoting 5hmC gains in specific gene bodies. SIGNIFICANCE: This work emphasizes the importance of epigenome plasticity in cancer development and highlights the involvement of druggable epigenetic factors in cancer.

Feline herpesvirus ulcerative dermatitis: an atypical case?

BACKGROUND: Feline herpesvirus ulcerative dermatitis is an uncommon skin disease in cats, with a predominantly facial distribution characterized by massive infiltration of eosinophils and, occasionally, predominant neutrophils. OBJECTIVE: To describe the clinical and histopathological features of a putative atypical case of feline herpesvirus dermatitis. ANIMAL: A 10-month-old, intact male, European cat was presented with chronic monolateral ulcerative dermatitis with adherent crusts on the left pinna. The lesion had been present for six months and worsened after the administration of corticosteroids. METHODS: Clinical and histopathological examination, immunohistochemistry, nested PCR and transmission electron microscopy (TEM). RESULTS: Histological examination of skin biopsies showed multifocal ulcerative and necrotic lesions, involving the superficial and deep dermis covered by thick haemorrhagic and serocellular crusts. The superficial, medium and deep dermis was heavily infiltrated with mast cells and plasma cells, with a lower number of neutrophils and eosinophils. In the nuclei of some cells in the deep dermis, whose histotype was unrecognizable with routine haematoxylin and eosin stain, intranuclear eosinophilic inclusion bodies were noticed. Nested PCR and TEM supported the hypothesis of FeHV-1-induced dermatitis. CONCLUSIONS AND CLINICAL IMPORTANCE: This case is noteworthy for the infrequent location on the pinna and the atypical histopathological features of the lesion, with a predominant infiltration of mast cells and plasma cells. Our findings suggest that herpesvirus dermatitis should be listed as a differential diagnosis in case of ulcerative dermatitis when the location and histological features are atypical.

Neoplastic diseases in the domestic ferret (Mustela putorius furo) in Italy: classification and tissue distribution of 856 cases (2000-2010).

BACKGROUND: The aim of this study was to describe the prevalence and tissue distribution of neoplasms in Italian ferrets, compared to the epidemiological data previously reported in USA and Japan. METHODS: Signalment and diagnoses of pathological submissions received between 2000 and 2010 were searched; cases with the diagnosis of neoplasm were selected and original sections reviewed to confirm the diagnosis. RESULTS: Nine-hundred and ten samples were retrieved, 690 of which included at least one tumour for a total of 856 tumours. Ferrets with multiple neoplasms were 134 (19.4%). Median age was 5 years, and F/M ratio was 0.99. Endocrine neoplasms were the most common. Other frequent tumours were cutaneous mast cell tumours, sebaceous tumours, and lymphomas. Cutaneous squamous cell carcinomas (SCC) were consistently associated with sebaceous tumours. Twenty-four abdominal spindle cell tumours with an undefined origin were observed. Lymphomas and islet cell tumours had a lower incidence compared with previous extra-European studies. DISCUSSION: Epidemiological information on ferret tumours derives from extra-European countries, mostly USA and Japan. In these countries similar distributions with minor discrepancies have been reported. Compared to previous reports, adrenal tumours were more frequent than pancreatic islet cell neoplasms, and a higher number of mesenchymal neoplasms arising from the adrenal capsule was noted. An unusual association between SCC and sebaceous gland neoplasms and a high number of intrabdominal spindle cell neoplasms with unclear primary origin were noted and grants further investigation. CONCLUSIONS: The tissue distribution of tumours recorded in this study paralleled previous findings in ferrets from USA and Japan. Some differences have been noted in the frequency of lymphoma, adrenal mesenchymal tumours and cutaneous tumours. Some tumours that are among the most common in other species seem to be uncommon in ferrets and are characterized by distinctive predilection sites.

Pericardial lymphoma in seven cats.

A presumed primary pericardial lymphoma was diagnosed in seven cats. Clinical findings at presentation included poor body condition, dehydration and dyspnoea. Thoracic diagnostic imaging was performed in six cases and revealed pleural effusion and a diffuse thickening of the pericardium. A cytological diagnosis of lymphoma was obtained in six cases; in four cases the diagnosis was confirmed at necropsy. Immunophenotyping was performed in six cases: three cases were classified as T-cell and three as B-cell lymphoma. Four cats did not receive any treatment. One cat received only prednisone and two cats received chemotherapy. Six cats lived 7-11 days, except for one cat that received a multi-drug chemotherapy protocol and was still alive at the time of writing (750 days after diagnosis). Primary pericardial lymphoma is a rare extranodal feline lymphoma that has never been described previously.